This invention relates to the field of pyridine and its derivatives and, particularly, to a process for dequaternizing pyridylethyl quaternary salts of substituted pyridine and bipyridine bases.
Pyridine, its characteristic formula being C.sub.5 H.sub.5 N, has been long recognized as the parent ring system of a large number of naturally occuring products and important industrial, pharmaceutical and agricultural chemicals. It is an aromatic compound and, much like benzene, gives rise to a large number of substituted homologs and derivatives, many of which are found in the light- and middle-oil fractions of coal tar and are commonly known and referred to as pyridine bases. Bipyridyl compounds, generally categorized by their 2,2'-, 3,3'- and 4,4'- connections, are one such specific group of pyridine homologs and derivatives and have themselves been generally known to the art for many years.
In industrial applications, it is often desirable to transform or change one substituted pyridine base to a second substituted pyridine base either because of the greater availability of the first or because of the critical need of the second base for a given application. Known means for attempting such a transfer include both electrophilic and nucleophilic substitution reactions in addition to the coupling reaction which produces a bipyridyl, or bipyridine, base from an initial substituted pyridine base. It has long been known to the art, however, that such transformation or change is often not feasible or practicable with the pyridine base in its free state.
In this regard, it has likewise long been known that both electrophilic and nucleophilic substituent transformation or change can be readily performed on the quaternary salts of a great majority of such pyridine bases. For example, in the area of electrophilic condensation, or substitution, 2- and 4-alkylpyridines containing alpha hydrogens undergo condensations with carbonyl compounds to give alcohols which in some cases react further to produce unsaturated compounds. The formation of 2- and 4- ethanolpyridines is an important example of this reaction in which the usual reaction conditions require high temperatures whether in the gas phase or under high pressure. The picolines have been shown to react in like fashion with aromatic aldehydes to give stilbazoles. Thus, when 2-picoline is heated with benzaldehyde in the presence of zinc chloride at 200.degree. C. for about 16 hours, 76% of the stilbazole is formed. See -C. Williams, et al., J. Org. Chem., v. 28, 387 (1963). The corresponding alkylpyridinium quaternary salts, on the other hand, react under much milder conditions as, for example, when 2-picoline methiodide in methanol was condensed at about 15.degree. C. with benzaldehyde, using piperidine as the catalyst, to produce 73% of the stilbazole quaternary salt. See Philips, J. Org. Chem., v. 12, 333 (1947).
In like fashion, the quaternary salts of alkylpyridines have been shown to react with ketones, esters, nitriles, anhydrides, alkylhalides and arylhalides in the presence of a weak base while the free pyridine bases require a strong alkali metal derivative such as sodamide. It is believed the hydrogens on the carbon alpha to the pyridine ring are more easily removed by mild organic bases such as secondary and tertiary amines in the case of the quaternary salts to produce anhydrobases which act as enamines and can be condensed with a number of electrophiles. Thus, the anhydrobase of 2-picoline methiodide condenses readily with acid chlorides, isocyanates, alkylhalides and carbon disulfide. Compare Klingsberg, v. 12, Chapter VII with Baker & McEvoy, J. Org. Chem., v. 20, 118 (1955). Also, compare Weiss & Hauser, J. Am. Chem. Soc., v. 71, 2026 (1949) with Adamcik & Flores, J. Org. Chem., v. 29, 572 (1964) regarding the Michael additions of alkylpyridines and their quaternary salts.
Similar conclusions have been reached with regard to the comparison of nucleophilic substitution of various substituted pyridine bases with their quaternary salts. For example, it is reported that the relative rates of reaction of 2-chloropyridine and 1-methyl-2-chloropyridinium iodide with - sodium methoxide in methanol at 50.degree. C. are 3.3.times.10.sup.-4 and 1.5.times.10.sup.5, respectively, thereby illustrating that a quaternary salt can react 5.times.10.sup.8 times faster than the corresponding free pyridine base. See Liveris & Miller, J. Chem. Soc., 3486 (1963).
In addition, halopyridinium salts readily undergo nucleophilic amination at room temperature or at slightly elevated temperatures in refluxing methanol in harsh contrast to the rather rigorous conditions required for amination of corresponding free 2- and 4-halopyridine bases. Compare Haack, Ger. Off. 595, 361 C.A. 28:4069 (1934) and Michaelis & Millman, Ann., v. 354, 91 (1907) with Wilbaut & Brockman, Rec. Trav. Chim., v. 80, 309 (1961) and Hauser & Weiss, J. Org. Chem., v. 14, 310 (1949). Comparison of the replacement reaction of thiopyridine analogs with their quaternary salts gives similar results [compare Schmidt & Giessilman, Ber., vol. 93, 1590 (1960) with King & Ozoz, J. Org. Chem., vol. 20, 448 (1955)], much as the cyano analogs [Poziomek, J. Org. Chem., vol. 28, 590 (1963)] and the hydroxylation reaction [see Barlin & Benbow, J. Chem. Soc., Perkin II, 1385 (1925)].
Therefore, as evidenced above, it is well established that both electrophilic and nucleophilic substitution are much more readily and practically performed on the quaternary salts of such pyridine and bipyridine bases. In this regard, the prior art above indicates that such quaternary salts are generally formed by the addition or substitution of a methyl or other alkyl group on the 1-position of the pyridine ring. -
It has also long been known that quaternary salts of certain pyridine bases yield bipyridinium salts through coupling reactions upon treatment with a reducing reagent followed by an oxidizing reagent. In a like fashion, the quaternary salts of 4-cyanopyridines yield bipyridinium salts on treatment with sodium dithionite followed by either oxygen or iodine. See Kosower and Cotter, J. Amer. Chem. Soc., 86 5524 (1964); Winters, Smith and Cohen, J. Chem. Comm., 642 (1970).
A major problem experienced with the use of quaternary salts to achieve coupling or electrophilic or nucleophilic substitution is that of regeneration of the free pyridine or bipyridine base following the transformation reaction. The methods previously workable for ammonium salts have proven totally unsatisfactory in this regard; and until recently, no general methods have existed for the dealkylation of the quaternary salts of pyridine and its bases, as discussed above.
However, soft nucleophiles such as triphenylphosphine (PPh.sub.3) and dimethylformamide (DMF) have now been reported to dealkylate the methyl quats of certain pyridine bases. See T. L. Ho, Synth. Commun., vol. 3, 99 (1973); Aumann & Deady, J. Chem. Soc. Chem. Commun., 32 (1973). Such reagents have been used both separately, as documented in Kutney and Greenhouse, Synth. Commun., v. 5(2), 119-24 (1975) and Aumann & Deady, supra, and in combination, as reported in Berg, Gallow, & Metzger, J. Org. Chem., vol. 41, 2821 (1976). In addition, T. L. Ho reported in his article, supra, the dealkylation of a pyridinium methiodide salt by refluxing the quaternary salt in DMF combined with 1,4-Diazabicyclo[2.2.2.] octane. -
All of these prior art methods, or processes, for the dealkylation of quaternary pyridinium salts have major disadvantages both in their yields and costs of operation. In the case of triphenylphosphine, the reagent is converted to the salt, CH.sub.3 -PPh.sub.3 I, making recovery of the reagent very difficult and expensive at best. The DMF methods, on the other hand, give low yields or require long reaction times, as evidenced in the Aumann & Deady article, supra, thus making the methods impractical for commercial use. Also, the end products of the reaction are not readily recyclable.
A further known quaternary salt, in contrast to the methyl and other alkyl salts discussed above, is the pyridylethyl quaternary salt prepared by the method disclosed in the Cislak patent, U.S. Pat. No. 2,512,789. Cislak also worked with dipyridyl, or bipyridyl, quaternary salts as disclosed in his later patent, U.S. Pat. No. 3,049,547. While his patents state that the preparation of monochloride salts occurs, it has been subsequently learned that the relevant examples of the Cislak patents, if followed, actually produce the acid salt of the compounds formed (i.e., chloride hydrochloride compounds). Little work has been done with these pyridylethyl quaternary salts, however, and applicants are aware of no known process for their dequaternization.
Therefore, although quaternary salts provide important media for the electrophilic and nucleophilic substitution of various pyridine bases and for the coupling reactions to form bipyridine bases, their importance is substantially lessened by the fact that once formed, and the intermediate substitution steps completed, there has been no known process for simply and efficiently dequaternizing the salts to free the new substituted bases.